Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12-FK506 in Cryptococcus neoformans
| Autor: | D S, Fox, M C, Cruz, R A, Sia, H, Ke, G M, Cox, M E, Cardenas, J, Heitman |
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| Rok vydání: | 2001 |
| Předmět: |
Recombination
Genetic Base Sequence Sequence Homology Amino Acid Virulence Calcineurin Genes Fungal Molecular Sequence Data Cryptococcosis Tacrolimus Binding Protein 1A Protein Structure Secondary Tacrolimus Fungal Proteins Heating Disease Models Animal Mice Mice Inbred DBA Mutagenesis Cryptococcus neoformans Animals Humans Amino Acid Sequence DNA Fungal |
| Zdroj: | Molecular microbiology. 39(4) |
| ISSN: | 0950-382X |
| Popis: | Calcineurin is a Ca2+-calmodulin-regulated protein phosphatase that is the target of the immunosuppressive drugs cyclosporin A and FK506. Calcineurin is a heterodimer composed of a catalytic A and a regulatory B subunit. In previous studies, the calcineurin A homologue was identified and shown to be required for growth at 37 degrees C and hence for virulence of the pathogenic fungus Cryptococcus neoformans. Here, we identify the gene encoding the calcineurin B regulatory subunit and demonstrate that calcineurin B is also required for growth at elevated temperature and virulence. We show that the FKR1-1 mutation, which confers dominant FK506 resistance, results from a 6 bp duplication generating a two-amino-acid insertion in the latch region of calcineurin B. This mutation was found to reduce FKBP12-FK506 binding to calcineurin both in vivo and in vitro. Molecular modelling based on the FKBP12-FK506-calcineurin crystal structure illustrates how this mutation perturbs drug interactions with the phosphatase target. In summary, our studies reveal a central role for calcineurin B in virulence and antifungal drug action in the human fungal pathogen C. neoformans. |
| Databáze: | OpenAIRE |
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